BACKGROUND: Megestrol acetate (MA) is a synthetic progestin commonly used to promote weight gain in malnourished older individuals. In small studies, MA administration has been associated with reduced serum cortisol concentrations in patients with cancer or AIDS. The impact of MA on the pituitary secretion of adrenocorticotropic hormone (ACTH) and other hormones is unclear, and the prevalence and extent of hypocortisolemia in older individuals after MA treatment is unknown. A randomized, placebo-controlled study of the effects of testosterone (T) and resistance training (RT) on body composition after MA administration in older men has been reported previously. OBJECTIVE: The purpose of this post hoc analysis was to examine the effect of 12 weeks of MA on pituitary function and end-organ hormone secretion in healthy older individuals using frozen serum samples from that study. METHODS: The previous study was conducted at the Department of Geriatrics, Donald W. Reynolds Center on Aging and the General Clinical Research Center at The University of Arkansas for Medical Sciences, Little Rock, Arkansas. Healthy male volunteers aged 60 to 85 years were recruited from the center and were randomly assigned to 1 of 4 study groups: RT + T, T, RT + placebo (P), or P. Subjects enrolled in the RT groups underwent supervised upper- and lower-body strength-training exercises 3 d/wk at 80% of 1 repetition maximum. Subjects in the groups to receive T received injections of testosterone enanthate 100 mg i.m. QW for 12 weeks. Subjects receiving P were given 1-mL saline injections i.m. QW for 12 weeks. All subjects received MA 800 mg p.o. QD concurrently for 12 weeks. For the present analysis, serum concentrations of the pituitary hormones follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), ACTH, prolactin (PRL), and luteinizing hormone (LH), as well as the end-organ hormones estradiol (E2), cortisol, free T4, and T, were measured in samples obtained at baseline (week 0) and after 12 weeks of MA treatment. RESULTS: Serum samples from 21 men (mean [SD]age, 67.0 [7.3]years; mean [SD] body mass index, 23.1 [10.4] kg/m2; mean [SD] percentage of body fat, 22.5% [8.8%]; RT + T, T, RT + P, and P groups, n = 4, 5, 6, and 6 subjects, respectively) were available from the original study. The mean percentage changes from baseline in serum pituitary hormone concentrations after 12 weeks of MA administration were as follows: TSH, -14.7%; ACTH, -89.5%; PRL, 162.2%; and LH, -49.0%; (P = 0.03, <0.001, <0.001, and <0.001, respectively). The mean (SD) percentage changes from baseline in serum end-organ hormone concentrations with MA at 12 weeks were as follows: E2, 181.6%; and cortisol, -90.8% (both, P < 0.001). In the P and RT + P groups, the mean percentage changes from baseline in T were -84% and -85%, respectively (both, P < 0.001). FSH and free T4 concentrations were not significantly changed. CONCLUSIONS: This analysis of serum samples from healthy older men suggests that MA administration significantly affected the secretion of several pituitary hormones and end-organ hormone synthesis. Most notably, ACTH secretion and serum cortisol levels were statistically significantly suppressed in 20 of 21 subjects, without the development of clinically significant adrenal suppression.